A Perspective on Roles Played by Innate and Adaptive Immunity in the Pathobiology of Neurodegenerative Disorders

Gendelman, Howard Eliot; Mosley, R. Lee

doi:10.1007/s11481-015-9639-4

Cited by 39 publications

(50 citation statements)

References 69 publications

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“…The immunological (and low inflammatory) alterations in sAD and in other NDD are well known. 19 The origin and intensity of these modifications attributed to sAD could be diverse. There are works indicating that early in the central nervous system (CNS) development, genetic and epigenetic modifications occur, and they are related to the immunological hypothesis.…”

Section: Rationalementioning

confidence: 99%

Salivary lactoferrin as biomarker for Alzheimer's disease: Brain‐immunity interactions

Bermejo‐Pareja

Ser

Valentí

et al. 2020

Alzheimer's & Dementia

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Objective We aim to explain why salivary lactoferrin (Lf) levels are reduced in patients suffering mild cognitive impairment (MCI) and sporadic Alzheimer's disease (sAD).1 We also will discuss if such Lf decrease could be due to a downregulation of the sAD associated systemic immunity. Background Several non‐neurological alterations have been described in sAD, mainly in skin, blood cell, and immunological capacities. We reviewed briefly the main pathophysiological theories of sAD (amyloid cascade, tau, unfolder protein tau, and amyloid deposits) emphasizing the most brain based hypotheses such as the updated tau‐related neuron skeletal hypothesis; we also comment on the systemic theories that emphasize the fetal origin of the complex disorders that include the low inflammatory and immunity theories of sAD. New/updated hypothesis Lf has important anti‐infectious and immunomodulatory roles in health and disease. We present the hypothesis that the reduced levels of saliva Lf could be an effect of immunological disturbances associated to sAD. Under this scenario, two alternative pathways are possible: first, whether sAD could be a systemic disorder (or disorders) related to early immunological and low inflammatory alterations; second, if systemic immunity alterations of sAD manifestations could be downstream of early sAD brain affectations. Major challenges for the hypothesis The major challenge of the Lf as early sAD biomarker would be its validation in other clinical and population‐based studies. It is possible the decreased salivary Lf in early sAD could be related to immunological modulation actions, but other different unknown mechanisms could be the origin of such reduction. Linkage to other major theories This hypothesis is in agreement with two physiopathological explanations of the sAD as a downstream process determined by the early lesions of the hypothalamus and autonomic vegetative system (neurodegeneration), or as a consequence of low neuroinflammation and dysimmunity since the early life aggravated in the elderly (immunosenescence).

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Section: Rationalementioning

confidence: 99%

Salivary lactoferrin as biomarker for Alzheimer's disease: Brain‐immunity interactions

Bermejo‐Pareja

Ser

Valentí

et al. 2020

Alzheimer's & Dementia

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“…In this progressive degenerative movement disorder, the key roles played by the subsets of CD4 + cells, especially the Treg whose number or activity is reduced in this pathology, have recently been highlighted. This, together with microglial activation, leads to changes in the microenvironment of the affected brain with oxidative stress, inflammation, and defective protein folding [295][296][297].…”

Section: Central Nervous System Diseasesmentioning

confidence: 99%

A Clinical Approach for the Use of VIP Axis in Inflammatory and Autoimmune Diseases

Martı́nez

Juarranz

Gutiérrez‐Cañas

et al. 2019

IJMS

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The neuroendocrine and immune systems are coordinated to maintain the homeostasis of the organism, generating bidirectional communication through shared mediators and receptors. Vasoactive intestinal peptide (VIP) is the paradigm of an endogenous neuropeptide produced by neurons and endocrine and immune cells, involved in the control of both innate and adaptive immune responses. Exogenous administration of VIP exerts therapeutic effects in models of autoimmune/inflammatory diseases mediated by G-protein-coupled receptors (VPAC1 and VPAC2). Currently, there are no curative therapies for inflammatory and autoimmune diseases, and patients present complex diagnostic, therapeutic, and prognostic problems in daily clinical practice due to their heterogeneous nature. This review focuses on the biology of VIP and VIP receptor signaling, as well as its protective effects as an immunomodulatory factor. Recent progress in improving the stability, selectivity, and effectiveness of VIP/receptors analogues and new routes of administration are highlighted, as well as important advances in their use as biomarkers, contributing to their potential application in precision medicine. On the 50th anniversary of VIP’s discovery, this review presents a spectrum of potential clinical benefits applied to inflammatory and autoimmune diseases.

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“…In agreement with our findings in α-syn tg mice, postmortem brain tissues from DLB patients also displayed increased infiltration of CD4 + helper T cells and CD1d + NKT cells. In the past, studies on neuroinflammation in AD and PD have generally focused on the abnormal activation of the innate immune system [29,[53][54][55][56]. However, recent evidence shows that alterations in the adaptive immune response might also contribute to inflammation and neurodegeneration in AD and age-related synucleinopathies [57][58][59].…”

Section: Discussionmentioning

confidence: 99%

Neuroinflammation is associated with infiltration of T cells in Lewy body disease and ɑ-synuclein transgenic models.

Iba

Kim

Sallin

et al. 2020

Preprint

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Background: ɑ-synuclein (ɑ-syn) is a presynaptic protein which progressively accumulates in neuronal and non-neuronal cells in neurodegenerative diseases such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy. Recent evidence suggests that aberrant immune activation may be involved in neurodegeneration in PD/DLB. While previous studies have often focused on the microglial responses, less is known about the role of the peripheral immune system in these disorders.Methods: To understand the involvement of the peripheral immune system in PD/DLB, we evaluated T cell populations in the brains of ɑ-syn transgenic (tg) mice (eg: Thy1 promoter line 61) and DLB patients.Results: Immunohistochemical analysis showed perivascular and parenchymal infiltration by CD3+/CD4+ helper T cells, but not cytotoxic T cells (CD3+/CD8+) or B cells (CD20+), in the neocortex, hippocampus, and striatum of ɑ-syn tg mice. CD3+ cells were found in close proximity to the processes of activated astroglia, particularly in areas of the brain with significant astrogliosis, microgliosis, and pro-inflammatory cytokines. In addition, a subset of CD3+ cells co-expressed interferon γ. Flow cytometric analysis of immune cells revealed that CD1d+ T cells were also increased in the brains of ɑ-syn tg mice and matched an expression profile consistent with natural killer T cells. In post-mortem DLB brains, we similarly detected CD3+ T cells that expressed CD4+ or CD1d+ in close proximity with blood vessels.Conclusion: These results suggest that infiltrating adaptive immune cells play an important role in neuroinflammation and neurodegeneration in synucleinopathies and that modulating peripheral T cells may be a viable therapeutic strategy for PD/DLB.

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A Perspective on Roles Played by Innate and Adaptive Immunity in the Pathobiology of Neurodegenerative Disorders

Cited by 39 publications

References 69 publications

Salivary lactoferrin as biomarker for Alzheimer's disease: Brain‐immunity interactions

Salivary lactoferrin as biomarker for Alzheimer's disease: Brain‐immunity interactions

A Clinical Approach for the Use of VIP Axis in Inflammatory and Autoimmune Diseases

Neuroinflammation is associated with infiltration of T cells in Lewy body disease and ɑ-synuclein transgenic models.

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